1,2,3',5'-tetrahydro-2'h-spiro[indole-3,1'-pyrrolo[3,4-C]pyrrole]-2,3'-dione compounds as therapeutic agents activating TP53

Abstract

The invention relates to 1,2,3′,5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione compounds represented by formula (I), wherein all symbols and variables are as defined in the description. The compounds can find use in a method of prevention and/or treatment of diseases selected from the group consisting of cancer, immune diseases, inflammatory conditions, allergic skin diseases associated with excessive proliferation, blinding disease and viral infections.

The invention claimed is: 
     
       1. A compound having the following structure 
       
         
           
           
               
               
           
         
         wherein
 R 1  is meta-halo-phenyl that is unsubstituted or substituted by one to two substituents independently selected from the group consisting of halogen, —OH, —NH2, —NO 2 , —CN, —C 1 -C 6 -alkyl, —O—(C 1 -C 6 -alkyl), —S—(C 1 -C 6 -alkyl), —C(O)O—(C 1 -C 6 -alkyl), —NH (C 1 -C 6 -alkyl), and —N(C 1 -C 6 -alkyl) 2 , 
 R 2  and R 3  are independently H or halogen; 
 R 4  is —C 1 -C 6 -alkyl; 
 R 7  is —OCH 3 ; 
 Z is C—R 8  or N, Y is C—R 9  or N, with the proviso that Z is not C—R 8  and Y is not C—R 9  in the same compound, 
 R 5 , R 6 , R 8 , R 9  are independently H, halogen, —OCH 3 , —NH(CH 3 ), or —N(CH 3 ) 2 , 
 or a salt thereof. 
 
       
     
     
       2. The compound of  claim 1 , wherein
 R 1  is meta-halo-phenyl that is unsubstituted or substituted by one to two substituents independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, —O—(C 1 -C 6 -alkyl), —NH (C 1 -C 6 -alkyl), and N(C 1 -C 6 -alkyl) 2 . 
 
     
     
       3. The compound of  claim 2 , wherein
 R 1  is meta-halo-phenyl that is unsubstituted or substituted by one to two substituents independently selected from the group consisting of halogen, —CH 3 , —OCH 3 , —NH (CH 3 ), and —N(CH 3 ) 2 . 
 
     
     
       4. The compound of  claim 1 , wherein
 R 2  is H, and 
 R 3  is Cl. 
 
     
     
       5. The compound of  claim 1 , wherein
 R 4  is iso-propyl or iso-butyl. 
 
     
     
       6. The compound of  claim 1 , wherein Z and Y are both N. 
     
     
       7. The compound of  claim 1 , wherein
 Z is C—R 8  and Y is N. 
 
     
     
       8. The compound of  claim 6 , wherein R 5  and R 6  are both OMe. 
     
     
       9. The compound of  claim 7 , wherein
 R 8  is H, and 
 at least one of R 5  and R 6  is OMe, and the second is selected from the group consisting of H, —N(Me) 2  and OMe. 
 
     
     
       10. The compound of  claim 1 , which is:
 (1) 
 (3S)-6-chloro-2′-(3-chlorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (2) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrr olo[3,4-c]pyrrole]-2,3′-dione, 
 (3) 
 (3S)-6-chloro-2′-(5-chloro-2-methylphenyl)-6′-(propan-2-yl)-5′-(2, 4,6-t rimethoxypyrimidin-5-yl)-1, 2,3′, 5′-tetrahydro-2′ H-spiro[indole-3,1′-p yrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (4) 
 (3S)-6-chloro-2′-(3-chloro-4-fluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrr olo[3,4-c]pyrrole]-2,3′-dione, 
 (5) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-6′-(propan-2-yl)-5′-(2, 4,6-t rimethoxypyrimidin-5-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-p yrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (6) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-[6-(dimethylamino)-4-met hoxypyridin-3-yl]-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indo le-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (7) 
 (3S)-6-chloro-2′-(3,4-difluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (8) 
 (3S)-6-chloro-2′-(3,4-difluorophenyl)-5′-(4,6-dimethoxypyridin-3-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (9) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-(4,6-dimethoxypyridin-3-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrol o[3,4-c]pyrrole]-2,3′-dione, 
 (10) 
 (3S)-6-chloro-2′-(5-chloro-2,4-difluorophenyl)-5′-(2,4-dimethoxypyrimi din-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, or 
 (11) (3S)-6′-(butan-2-yl)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione. 
 
     
     
       11. The compound of  claim 6  which is:
 (1) 
 (3S)-6-chloro-2′-(3-chlorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (2) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrr olo[3,4-c]pyrrole]-2,3′-dione, 
 (3) 
 (3S)-6-chloro-2′-(5-chloro-2-methylphenyl)-6′-(propan-2-yl)-5′-(2, 4,6-t rimethoxypyrimidin-5-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-p yrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (4) 
 (3S)-6-chloro-2′-(3-chloro-4-fluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrr olo[3,4-c]pyrrole]-2,3′-dione, 
 (5) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-6′-(propan-2-yl)-5′-(2, 4,6-t rimethoxypyrimidin-5-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-p yrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (7) 
 (3S)-6-chloro-2′-(3,4-difluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (10) 
 (3S)-6-chloro-2′-(5-chloro-2,4-difluorophenyl)-5′-(2,4-dimethoxypyrimi din-5-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, or 
 (11) (3S)-6′-(butan-2-yl)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-(2,4-dimethoxypyrimidin-5-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione. 
 
     
     
       12. The compound of  claim 7  which is:
 (6) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-[6-(dimethylamino)-4-met hoxypyridin-3-yl]-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indo le-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, 
 (8) 
 (3S)-6-chloro-2′-(3,4-difluorophenyl)-5′-(4,6-dimethoxypyridin-3-yl)-6 ′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrolo[3,4-c]pyrrole]-2,3′-dione, or 
 (9) 
 (3S)-6-chloro-2′-(5-chloro-2-fluorophenyl)-5′-(4,6-dimethoxypyridin-3-yl)-6′-(propan-2-yl)-1, 2,3′, 5′-tetrahydro-2′H-spiro[indole-3,1′-pyrrol o[3,4-c]pyrrole]-2,3′-dione. 
 
     
     
       13. The compound of  claim 3 , wherein R 1  is meta-halo-phenyl that is substituted by one to two halogen. 
     
     
       14. A compound having the following structure 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       15. A compound having the following structure 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       16. A pharmaceutical composition comprising as an active ingredient a compound as defined in  claim 1 , in combination with at least one pharmaceutically acceptable excipient. 
     
     
       17. A pharmaceutical composition comprising as an active ingredient a compound as defined in  claim 14 , in combination with at least one pharmaceutically acceptable excipient. 
     
     
       18. A method of treating osteosarcoma comprising administering a therapeutically effective amount of the compound of  claim 1  to a subject in need thereof. 
     
     
       19. A method of treating osteosarcoma comprising administering a therapeutically effective amount of the compound of  claim 14  to a subject in need thereof. 
     
     
       20. A method of treating osteosarcoma comprising administering a therapeutically effective amount of the compound of  claim 15  to a subject in need thereof.